Title

Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: Implications for therapy

Document Type

Journal Article

Publication Date

6-1-2012

Journal

Leukemia

Volume

26

Issue

6

DOI

10.1038/leu.2011.340

Keywords

HDAC3; LBH589; Lymphoma; Mcl-1; STAT3

Abstract

Diffuse large B-cell lymphoma (DLBCL) with an activated B-cell (ABC) gene-expression profile has been shown to have a poorer prognosis compared with tumors with a germinal center B-cell type. ABC cell lines have constitutive activation of STAT3; however, the mechanisms regulating STAT3 signaling in lymphoma are unknown. In studies of class-I histone deacetylase (HDAC) expression, we found overexpression of HDAC3 in phospho STAT3-positive DLBCL and the HDAC3 was found to be complexed with STAT3. Inhibition of HDAC activity by panobinostat (LBH589) increased p300-mediated STAT3 Lys685 acetylation with increased nuclear export of STAT3 to the cytoplasm. HDAC inhibition abolished STAT3 Tyr705 phosphorylation with minimal effect on STAT3 Ser727 and JAK2 tyrosine activity. pSTAT3 Tyr705-positive DLBCLs were more sensitive to HDAC inhibition with LBH589 compared with pSTAT3 Tyr705-negative DLBCLs. This cytotoxicity was associated with downregulation of the direct STAT3 target Mcl-1. HDAC3 knockdown upregulated STAT3 Lys685 acetylation but prevented STAT3 Tyr705 phosphorylation and inhibited survival of pSTAT3-positive DLBCL cells. These studies provide the rationale for targeting STAT3-positive DLBCL tumors with HDAC inhibitors. © 2012 Macmillan Publishers Limited.

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